Synthesis of benzocyclic ketones via palladium-catalyzed cyclization of ω-(2-iodoaryl)alkanenitriles

Article abstract of DOI:10.1016/S0040-4039(02)00247-2

An efficient procedure for the synthesis of 2,2-disubstituted benzocyclic ketones by intramolecular carbopalladation of nitriles has been developed. The cyclization of substituted 3-(2-iodoaryl)propanenitriles affords indanones in high yields. The reactio

Full text of DOI:10.1016/S0040-4039(02)00247-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2133–2136
Synthesis of benzocyclic ketones via palladium-catalyzed
cyclization of v-(2-iodoaryl)alkanenitriles
Alexandre A. Pletnev and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Received 15 January 2002; accepted 1 February 2002
Abstract—An efficient procedure for the synthesis of 2,2-disubstituted benzocyclic ketones by intramolecular carbopalladation of
nitriles has been developed. The cyclization of substituted 3-(2-iodoaryl)propanenitriles affords indanones in high yields. The
reaction is compatible with a wide variety of functional groups. This chemistry has been extended to the synthesis of tetralones,
a 9-fluorenone and a cyclopentenone. © 2002 Elsevier Science Ltd. All rights reserved.
Benzocyclic ketones are versatile and useful synthetic
intermediates in the agrochemical and pharmaceutical
industries.1 1-Indanone derivatives exhibit useful bio-
logical activity (e.g. antihypertensive or bronchodila-
tory)1a,2 and also serve as important building blocks in
the synthesis of many natural products3 and medicinal
substances.4 a-Tetralones represent a valuable class of
starting materials and intermediates for the synthesis of
biologically active lignans,5 cytotoxic antileukemic alka-
loids,6 and other pharmaceutical preparations.1d,7 Clas-
sical means for the synthesis of benzocyclic ketones
include intramolecular Friedel–Crafts acylation,6a,8
Vilsmeier–Haack cyclization,1c and variations of car-
bonylation processes.9 While widely used and applica-
ble to many substrates, these methods often require
strong acidic conditions or reagents that restrict the
variety of functional groups that are tolerated. Com-
plex benzocyclic ketones have been synthesized by
derivatization of simple indanones and tetralones,10 or
via indirect, highly specific routes to key targets.7,11
route to 2,2-disubstituted indanones (I, n=1) and
related benzocyclic ketones (Eq. (1)).
(1)
Our initial attempt to apply our previous nitrile annula-
tion conditions12 to the cyclization of 2,2-dimethyl-3-(2-
iodophenyl)propanenitrile (1) met with only partial
success as GC–MS analysis of the reaction mixture
after 24 h revealed the presence of approximately equal
amounts of the target, 2,2-dimethyl-1-indanone (2), and
unreacted 1. A longer reaction time failed to change
this ratio or bring about more complete conversion of
the starting material. We then focused our optimization
efforts on reaction conditions similar to those employed
by Yang et al. in their study of the intramolecular
addition of an arylpalladium to a proximal alkeneni-
trile.13 The following optimal reaction conditions have
subsequently been established: 0.25 mmol of the v-(2-
iodoaryl)alkanenitrile, 10 mol% Pd(OAc)2, 20 mol%
PPh3, and 1.2 equiv. of NEt3 in 5 ml of a 9:1 DMF–
water mixture are stirred at 130°C under Ar for an
appropriate amount of time. It should be noted that an
inert atmosphere is not essential for the success of the
procedure as the product yields decrease only slightly
when the reaction is conducted in air. We have also
found that formation of the cyclization products is
often accompanied by some reduction of the car-
bonꢀiodine bond of the starting materials (Eq. (1)),14
which is not uncommon for palladium-catalyzed reac-
tions of aryl halides.15 The results of our studies on the
scope and limitations of this process are summarized in
Table 1.
Recently, we reported the novel carbopalladation of a
cyano group, observing for the first time the addition of
alkenyl- and alkylpalladium species across the car-
bonꢀnitrogen triple bond of arenenitriles.12 This process
afforded a convenient synthesis of carbocycles, such as
indenones and 2-aminonaphthalenes, by the palladium-
catalyzed annulation of aromatic nitriles. Herein, we
wish to report that the palladium-catalyzed cyclization
of appropriately substituted v-(2-iodoaryl)alkane-
nitriles has been found to be an efficient and general
* Corresponding author. Tel.: +1-515-294-4660; fax: +1-515-294-0105;
e-mail: larock@iastate.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00247-2

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A. A. Pletne6, R. C. Larock / Tetrahedron Letters 43 (2002) 2133–2136
Table 1. Synthesis of benzocyclic ketones by the Pd-catalyzed cyclization of v-(2-iodoaryl)alkanenitriles (Eq. (1))a
Under the optimized reaction conditions, 1 readily
cyclizes to afford 2,2-dimethyl-1-indanone (2) in a high
yield (Table 1, entry 1). Equally successful is the
cyclization of 1-(2-iodobenzyl)cyclohexanecarbonitrile
(3), producing the spirocyclic indanone 4 (entry 2), the
skeleton of which is related to several pharmaceutical
substances.1a,3b,4a 2,2-Diphenyl-1-indanone (6) was
obtained in a 92% yield (entry 3), despite our concern
monosubstituted indanones. However, this limitation
can be overcome by the decarboxylation of 1-indanone-
2-carboxylate esters,17 such as 10, which is readily
prepared from methyl 2-cyano-3-(2-iodophenyl)-2-
methylpropanoate (9) using our cyclization procedure
(entry 5).
The cyclization seems to be reasonably general with
respect to the substituents in the alkyl chain and the
aromatic ring (entries 1–9) and tolerant of a variety of
functional groups (entries 5–9). The indanones 10, 12,
14, 16 and 18 have been obtained from the correspond-
ing substrates containing ester, ether, nitro, hydroxy
and keto functionalities. The electron-rich aryl iodide
11 produced the corresponding indanone 12 in a yield
comparable to that obtained with the parent system 1,
although this cyclization required a longer reaction time
(entry 6), presumably due to the more sluggish oxida-
tive addition of 11 to the Pd(0) catalyst. The lower yield
that
2-aryl-3-(2-iodophenyl)propanenitriles
might
undergo a potential side reaction whereby the initially
obtained arylpalladium intermediate (see the proposed
mechanism below) would couple with one of the aryl
substituents to afford a dihydrophenanthrene deriva-
tive.16 Cyclization of the secondary nitrile 7 resulted in
only a modest yield of the target 2-ethyl-1-indanone (8,
entry 4). The major product proved to be the dehalo-
genated starting material. This represents a limitation
of the current procedure, as so far no conditions have
been found that substantially increase the yield of 2-

A. A. Pletne6, R. C. Larock / Tetrahedron Letters 43 (2002) 2133–2136
2135
in the cyclization of the electron-poor nitrile 13 (entry
7) is probably caused by the reduced nucleophilicity of
the arylpalladium intermediate involved in attack on
the cyano group (vide infra).
iodoaryl)alkanenitriles. The procedure tolerates a wide
variety of functional groups and may be adapted for
the indirect synthesis of 2-monosubstituted indanones.
The suitability of this methodology for the preparation
of a 9-fluorenone and a cyclopentenone has also been
demonstrated.
The current cyclization appears to be applicable to the
synthesis of benzocyclic ketones other than indanones.
Thus, 4-(2-iodophenyl)-2,2-dimethylbutanenitrile (19)
has been found to afford tetralone 20 in a good yield
(entry 10). The efficacy of this cyclization in six-mem-
bered ring formation is remarkable considering that the
greater conformational flexibility present in 19 must
significantly reduce the likelihood of achieving the con-
formation necessary for intramolecular addition of the
arylpalladium to the cyano group.
Acknowledgements
We thank the donors of the Petroleum Research Fund,
administered by the American Chemical Society, for
partial support of this research and Kawaken Fine
Chemicals Co., Ltd., and Johnson Matthey, Inc., for
donating the palladium acetate.
Other cyclic ketones can be readily prepared by this
methodology. For example, 9-fluorenone (22) was
obtained from the biaryl substrate 21 in what we
believe to be the first example of the addition of an
arylpalladium to an arenenitrile (entry 11). Finally, the
reaction scope has been extended to include the vinylic
substrate 23, the cyclization of which resulted in the
formation of the cyclopentenone 24 in high isolated
yield (entry 12).
References
1. (a) Bhattacharya, A.; Segmuller, B.; Ybarra, A. Synth.
Commun. 1996, 26, 1775–1784; (b) Smonou, I.;
Orfanopoulos, M. Synth. Commun. 1990, 20, 1387–1397;
(c) Witiak, D. T.; Williams, D. R.; Kakodkar, S. V. J.
Org. Chem. 1974, 39, 1242–1247; (d) Gutman, A. L.;
Etinger, M.; Nisnevich, G.; Polyak, F. Tetrahedron:
Asymmetry 1998, 9, 4369–4379.
We propose the mechanism illustrated in Scheme 1 for
this
palladium-catalyzed
cyclization
of
v-(2-
2. Galatsis, P.; Manwell, J. J.; Blackwell, J. M. Can. J.
iodoaryl)alkanenitriles. Oxidative addition of the aryl
iodide to a Pd(0) species, produced by reduction of
Pd(OAc)2, leads to the arylpalladium intermediate A.
The next step, carbopalladation, requires sufficient elec-
tron density on the palladium center in A for it to add
to the carbonꢀnitrogen triple bond, as well as close
proximity of the cyano group to this palladium center
(i.e. the conformation shown in Scheme 1). Addition of
the arylpalladium species A across the cyano group
affords an iminopalladium intermediate, which then
hydrolyzes to the corresponding ketone I. The Pd(II) is
then reduced again to Pd(0) that returns to the catalytic
cycle. Alternatively, the arylpalladium intermediate A
may undergo a reduction process, which results in
formation of the byproduct II. The exact mechanism of
this reduction, as well as the identity of the reagent
responsible for reducing intermediate A or for reduc-
tion of Pd(II) to Pd(0), are unknown at this time.
Chem. 1994, 72, 1656–1659.
3. (a) Sartori, G.; Maggi, R.; Bigi, F.; Porta, C.; Tao, X.;
Bernardi, G. L.; Ianelli, S.; Nardelli, M. Tetrahedron
1995, 51, 12179–12192; (b) Watanabe, M.; Morimoto, H.;
Tomoda, M.; Iwanaa, U. Synthesis 1994, 1083–1086.
4. (a) Lin, S.-K.; Rasetti, V. Helv. Chim. Acta 1995, 78,
857–865; (b) Harvey, A. L.; MacTavish, J.; Mullins, S. J.;
Proctor, G. R. J. Chem. Res. Synop. 1997, 420–421; (c)
Johansson, A. M.; Mellin, C.; Hacksell, U. J. Org. Chem.
1986, 51, 5252–5258.
5. (a) Yang, F. Z.; Trost, M. K.; Fristad, W. E. Tetrahedron
Lett. 1987, 28, 1493–1496; (b) Esteban, G.; Lopez-
Sanchez, M. A.; Martinez, M.; Plumet, J. Tetrahedron
1998, 54, 197–212.
6. (a) Ishii, H.; Chen, I.-S.; Ueki, S.; Masuda, T.; Morita,
K.; Ishikawa, T. J. Chem. Soc., Perkin 1 1987, 2415–
2420; (b) Vicario, J. L.; Badia, D.; Dominguez, E.; Car-
rillo, L. Tetrahedron: Asymmetry 2000, 11, 1227–1237; (c)
Yoshida, M.; Watanabe, T.; Ishikawa, T. Heterocycles
2001, 54, 433–436; (d) Patil, M. L.; Borate, H. B.; Ponde,
D. E.; Bhawal, B. M.; Deshpande, V. H. Tetrahedron
Lett. 1999, 40, 4437–4438.
In conclusion, we have developed a general and
efficient method for the synthesis of 2,2-disubstituted
benzocyclic ketones from readily prepared v-(2-
7. Liard, A.; Quiclet-Sire, B.; Saicic, R. N.; Zard, S. Z.
Tetrahedron Lett. 1997, 38, 1759–1762.
8. (a) Johnson, W. S. Org. React. 1944, 2, 114–177; (b)
Sangaiah, R.; Gold, A. J. Org. Chem. 1991, 56, 6717–
6720.
9. (a) Bruson, H. A.; Plant, H. L. J. Org. Chem. 1967, 32,
3356–3362; (b) Doyama, K.; Fujiwara, K.; Joh, T.;
Maeshima, K.; Takahashi, S. Chem. Lett. 1988, 901–904.
10. (a) Henin, F.; M’Boungou-M’Passi, A.; Muzart, J.; Pete,
J.-P. Tetrahedron 1994, 50, 2849–2864; (b) Ryan, J. H.;
Stang, P. J. Tetrahedron Lett. 1997, 38, 5061–5064.
11. (a) Borg, R. M.; Berry, M. A.; Mangion, D. Tetrahedron
Lett. 1994, 35, 8485–8488; (b) Pinnick, H. W.; Brown, S.
Scheme 1.

2136
A. A. Pletne6, R. C. Larock / Tetrahedron Letters 43 (2002) 2133–2136
P.; McLean, E. A.; Zoller, R. W., III J. Org. Chem. 1981,
46, 3758–3760.
12. Larock, R. C.; Tian, Q.; Pletnev, A. A. J. Am. Chem.
Soc. 1999, 121, 3238–3239.
13. (a) Yang, C.-C.; Tai, H.-M.; Sun, P.-J. J. Chem. Soc.,
Perkin Trans. 1 1997, 2843–2850; (b) Deng, J.-H.; Tai,
H.-M.; Yang, C.-C. J. Chin. Chem. Soc. 2000, 47, 327–
341.
chromatography, so the yields of all known products
were determined by analysis of the GC–MS and 1H
NMR spectral data obtained from the reaction mixtures.
15. (a) Quan, L. G.; Lamrani, M.; Yamamoto, Y. J. Am.
Chem. Soc. 2000, 122, 4827–4828; (b) Zask, A.; Helquist,
P. J. Org. Chem. 1978, 43, 1619–1620.
16. For an example of such a process, see: Qabaja, G.; Jones,
G. B. J. Org. Chem. 2000, 65, 7187–7194.
17. Larock, R. C. Comprehensive Organic Transformations,
2nd ed.; Wiley-VCH: New York, 1999; p. 1542.
14. Given the small scale of our reaction, it has sometimes
proven difficult to separate the two products by column